antioxidants

Editorial
Pros and Cons of Use of
Mitochondria-Targeted Antioxidants
Egor Y. Plotnikov 1,2 and Dmitry B. Zorov 1,2, *
1 A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University,
Moscow 119992, Russia
2 V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology,
Moscow 117997, Russia
* Correspondence: zorov@belozersky.msu.ru; Tel.: +7-495-939-5944




Received: 9 August 2019; Accepted: 15 August 2019; Published: 17 August 2019


Abstract: Mitochondrial targeting is a novel strategy, which addresses pathologies originating

from mitochondrial dysfunction. Here, one of the most potent therapeutics arises from the group
of mitochondria-targeted antioxidants, which specifically quench mitochondrial reactive oxygen
species (ROS). They show very high efficacy in the treatment of a diverse array of pathologies
encountered in this Special Issue of Antioxidants. However, despite very encouraging results in the use
of mitochondria-targeted antioxidants, the mechanistic principle of delivering these agents is, to some
extent, counterproductive to the goal of selectively treating a population of damaged mitochondria.
The main problem that arises is that injured mitochondria may carry a lower membrane potential
when compared with normal ones and as a result, injured mitochondria are capable of taking up less
therapeutic antioxidants than healthy mitochondria. Another problem is that the intracellular activity
of mitochondrial ROS differs from cytosolic ROS in that they carry specific intracellular functions
which are maintained at a delicate equilibrium and which may be disturbed under careless use
of antioxidant doses. Consequently, understanding the overall benefit of targeting dysfunctional
mitochondria in pathological tissue requires furthering the development of alternative techniques to
target mitochondria.

Keywords: mitochondria; oxidative stress; antioxidants

Apart from offering a cure, most types of therapeutic intervention can have numerous adverse side
effects, which can be the case with the use of antioxidants. The purpose of using antioxidants is to reduce
excessive levels of highly reactive oxidants most of which are represented by reactive oxygen species
(ROS). The ROS group consists mainly of unstable radicals (superoxide anion, hydroxyl anion and
singlet oxygen, including derivatives thereof) and hydrogen peroxide (reviewed in [1]). All these agents
have different oxidizing capacities and potential, possess distinct physical and chemical properties
which determine their distinct distribution within hydrophilic and hydrophobic environments and
which contribute largely to their substrate specificity. Nevertheless, we must emphasize that ROS are
an essential element of cell signaling, regulating vital biochemical processes within the cell, ultimately
regulating the processes of division, differentiation, growth, and neutralization or elimination of
unwanted cell parts or whole cells [2].
Homeostasis of ROS is one of the mandatory requirements for maintaining the viability of the
cellular system [3] and alterations in it are mainly caused by a local insult from a range of chemical,
physical and biological factors. As a result, a lesion focus may be formed which emits ROS in excessive
levels and becomes a trigger for the emergence of serious pathological conditions often associated with
inflammation and a high risk of tissue death [4].

Antioxidants 2019, 8, 316; doi:10.3390/antiox8080316 www.mdpi.com/journal/antioxidants

Antioxidants 2019, 8, 316 2 of 6

To some extent, the intracellular localization of oxidative stress is the main problem and in a
positive manner does, therefore, offer an appropriate therapeutic approach to its elimination. It is
fair to say that even in the absence of any oxidative challenge, an organism is a highly heterogeneous
system in terms of existing ROS levels. Slowly metabolizing tissues are most often characterized by a
low level of endogenous ROS in contrast to tissues with high metabolic activity, such as the heart or
brain. Nevertheless, even within these organs, which are composed of a diverse community of cells,
there is high heterogeneity in both the levels of ROS and in the activity levels of systems that maintain
normal ROS homeostasis [5–7]. By definition, high levels of ROS should be observed in the lung tissue,
which primarily makes contact with alien antigens from inhaled air at very high partial pressures of
oxygen [8,9]. To some extent, this is true for the intestinal tract as well, although it is characterized by
possessing low metabolic activity [10].
To suppress the oxidative burst, general antioxidants are therefore quite ubiquitously used.
Indeed, general antioxidants are administered orally, iv or intra-muscular, which eventually penetrate
into the blood and reach the targeted organ. However, upon using any of these forms of antioxidant
administration, healthy tissues other than the targeted organ, which have not experienced oxidative
damage, may be non-specifically targeted by the antioxidant [11,12].
Now that it has become common knowledge that mitochondria are one of the main generators of
ROS in the cell, it is also accepted that it is through this local “oxidative fire” arising from within the
mitochondria that gives rise to pathogenicity [13–15]. These arguments serve as a strong ideological
basis for the development of the concept in the use of mitochondria-targeted antioxidants. The principle
being developed is based on the proposal to use charged substances possessing a number of conjugated
double bonds, which permit the charge to be delocalized [16] particularly as the localization of a charge
can be the main obstacle in the penetration of ions through phospholipid membranes. This is due to
each localized charge in the aqueous phase being surrounded by a shell of oppositely charged ions and
water dipoles, which cannot cross the bilayer due to steric restrictions. Delocalization (spreading out)
of the primary charge solves the problem of penetration, which leads to the fact that cations possessing
delocalized charges can be accumulated in the mitochondrial matrix carrying a negative charge and
anions with delocalized charges can accumulate inside the sub-mitochondrial particles carrying a
positive charge [17,18]. Without exaggeration, these ions with delocalized charges formed a strong
basis for awarding the Nobel prize in 1978 to P. Mitchell, as a result of proving the chemiosmotic
hypothesis [19].
However, several decades later, it has become clear that penetrating cations can serve as
a locomotive for the transfer of therapeutic agents to the mitochondria. Historically, the first
proposition was to use locomotive conjugates made of penetrating cation and antioxidant molecules,
primarily quinone derivatives [20]. Once in the mitochondria, reduced quinones (ubiquinone or
plastoquinone derivatives) are oxidized, with plastoquinone derivatives being able to receive electrons
from the respiratory chain of mitochondria resulting in their reduction, thus making these compounds
renewable. Consequently, frenetic activity in developing derivatives of such compounds resumed
permitting the mitochondrial “oxidative fire” to be better controlled and even in some cases, completely
extinguished [21,22].
The conceptual drive to extinguish oxidative stress in pathological mitochondria was established
for a number of pathological processes associated with oxidative stress. For more than two decades of
experimental research into mitochondria-targeted antioxidants, a number of impressive beneficial effects
in the treatment of numerous pathologies associated with oxidative stress have been demonstrated
which offer a wide therapeutic concentration window [23–38]. For example, in this Special Issue
of Antioxidants a few successful examples are presented for the treatment of brain trauma [39],
age-related macular degeneration [40], light-induced retina damage [41], hearing loss [42], and neonatal
sepsis [43]. Related issues such as prevention of oxidative stress-induced mitochondrial dysfunction
by mitochondrial uncouplers [44], melatonin [45] and glutathione [46] and physiologic implications of
ROS production by a reverse electron transport [47] are also covered in the Special Issue. As we see,
Antioxidants 2019, 8, 316 3 of 6

the mitochondria-targeting concept is developing exponentially through the exploration of a variety of

vehicles and substances targeting the mitochondria with a view to restoring impaired mitochondrial
structure and functions.
However, mitochondrial targeting has also faced its fair share of problems and drawbacks.
The main problems faced stem from conflicts between theory and practice as the accumulation of
mitochondrial-targeted antioxidants should occur in direct proportion to the value of the mitochondrial
membrane potential (∆ψ), which serves to drive the accumulation of cations in a negatively charged
matrix. At the same time, there is evidence that the mitochondrial population is somewhat
heterogeneous in terms of ∆ψ and it is in pathological conditions that this heterogeneity is enhanced
due to the appearance of low-potential mitochondria. Consequently, the use of mitochondrial-directed
antioxidants meets a paradoxical challenge in that low-potential mitochondria do need quenching
for their internal oxidative stress but their uptake of such agents is poor by comparison to healthy
mitochondria which do not experience any problem with metabolism.
As a result, upon increasing antioxidant doses to permit the repair of pathological mitochondria
(especially toxic hyperpolarized mitochondria), normal mitochondria may also be affected negatively
as their levels of ROS may fall below their physiologically acceptable limit. Derived from this, it should
also be noted that in the scientific arena, the term “oxidative stress” is often used very broadly while
very little mention is made of “reductive stress”, which can be defined by the presence of unacceptably
low levels of ROS and which does not allow the normal physiological reactions to occur in the
“ROS-world” [4]. This makes it possible to include reductive stress (generalized or local) in the category
of no less pathogenic systems than oxidative stress. It is fair to mention that mitochondria-targeted
antioxidants will have the maximum effect on hyperpolarized mitochondria, which are also likely
to be toxic to cells. Redefining the consequences of ROS damage based on them occurring through
simultaneous variations in the levels of oxidative- or reductive-stresses allows us to therefore define
the pathologies of diseases arising from them with greater accuracy as well.
The problem of heterogeneity of the mitochondrial population in the cell is directly related to
the above-mentioned heterogeneity of ROS generation. As of yet, no regulatory mechanisms have
been defined that permit the discrimination between ROS species as being “good ROS” or “bad
ROS” as the detrimental effects of ROS are believed to be defined by their origins and what levels
they appear to be present in. There are many examples of mitochondrial (rather than cytosolic) ROS
that participate in a number of specific molecular signaling events and consequently, the ablation of
mitochondrial or cytoplasmic ROS below physiological thresholds can lead to deregulation or loss of
specific signaling cascades.
Thus, with all the obvious benefits of mitochondria-targeted antioxidants resulting from the
diverse origins of ROS distribution in the organism, organs, and cells, we have to be mindful of dosage,
timing, and modes of exposure for different pathologies since the heterogeneity of the mitochondrial
population has to be a central consideration. Alternatively, formulating an approach which does
not exploit the mitochondrial membrane potential to drive antioxidant accumulation by specifically
targeting unique mitochondrial components (such as oxidized cardiolipin) may offer a more specific
approach in treating a damaged population of mitochondria.

Author Contributions: Writing—Original Draft Preparation and Writing—Review and Editing, E.Y.P. and D.B.Z.
Funding: This work was supported by the Russian Science Foundation, Grant 19-14-00173.
Acknowledgments: We are grateful to the Editor-in-Chief Stanley Omaye and Editorial Board members for the
invitation to serve as guest editors for the Special Issue “Mitochondria-Targeted Antioxidants”. We are thankful to
all who accepted our call for articles to be included in this Special Issue.
Conflicts of Interest: The authors declare no conflict of interest.
Antioxidants 2019, 8, 316 4 of 6

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